Bullous pemphigoid is a chronic autoimmune subepidermal blistering disease caused by IgG autoantibodies directed against hemidesmossomal antigens (BP180 and BP230) at the dermal-epidermal junction, typically presenting with tense blisters on an erythematous base in elderly patients.

Exam domain	One-glance essentials
Definition / diagnosis	*Most common autoimmune blistering disease; usually affects older adults* ^[1] IgG against BP180/BP230 hemidesmosomes → subepidermal split → tense bullae ^[1]^[2]
Epidemiology / risks	Age > 60 years; associations include stroke, dementia and Parkinson disease ^[2] Review DPP-4 inhibitors and PD-1 inhibitors as important drug triggers ^[3]
Core mechanism	Autoantibody binding at the basement membrane activates complement → eosinophilic inflammation → subepidermal blister ^[1]^[2] Intact epidermal roof explains tense blisters and a negative Nikolsky sign
Clinical picture	*Intensely pruritic, tense bullae on an erythematous or urticarial base* ^[1] Pre-bullous urticaria/eczema may precede blisters; mucosal disease is less prominent than in pemphigus ^[2]^[3]
Investigations	Two biopsies: lesional H&E → subepidermal split with eosinophils; perilesional DIF → *linear IgG/C3 at the basement membrane* ^[1]^[3] Anti-BP180/BP230 serology supports diagnosis; salt-split skin shows epidermal-roof binding ^[2]
Management	*Prick tense blisters but do not de-roof; use non-adherent dressings* ^[3] Localised disease: superpotent topical corticosteroid; more extensive disease: doxycycline or systemic corticosteroid with a steroid-sparing agent ^[1]^[4]
Complications	Secondary bacterial/HSV infection and fluid or protein loss from widespread erosions ^[3] In frail older adults, infection and systemic-steroid toxicity drive mortality ^[2]^[4]
Prevention / follow-up	Stop an implicated drug where feasible; protect blister roofs and treat infection early ^[3] Before immunosuppression, screen HBsAg/anti-HBc; check G6PD before dapsone and TPMT before azathioprine ^[3]^[4]
Exam traps	*Urticarial lesions persisting > 24 hours in an older adult may be pre-bullous pemphigoid* ^[3] Tense + Nikolsky negative favours pemphigoid; flaccid + Nikolsky positive favours pemphigus ^[1]^[2] BP binds the salt-split roof; epidermolysis bullosa acquisita binds the floor ^[2]

References

^[1] Lecture slides: CFB (MED09) Dermatology (II).pdf, p9–11 ^[2] Senior notes: Ryan Ho Rheumatology.pdf, p152–154 ^[3] Lecture slides: Derm General Clerkship 2026 Part2.pdf, p2, p18–25 ^[4] Senior notes: Block A - Treatments for skin diseases (eczema, psoriasis and urticaria).pdf, p6

Bullous Pemphigoid

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterised by the production of autoantibodies (primarily IgG) directed against hemidesmosomal antigens — BP180 (BPAg2, type XVII collagen) and BP230 (BPAg1) — at the dermal–epidermal junction (DEJ) ^[1]^[2]^[3]. The name itself is informative:

"Bullous" = large fluid-filled blisters (bullae, > 0.5 cm)
"Pemphigoid" = "pemphigus-like" (from Greek pemphix = blister); the suffix "-oid" means "resembling" — it resembles pemphigus but is fundamentally different because the split occurs below the epidermis (subepidermal) rather than within it (intraepidermal)

The hallmark is tense, intact bullae on an erythematous, urticarial base, typically in an elderly patient ^[1]^[2]^[3]. Because the blister roof consists of the full-thickness epidermis (the split is at the basement membrane zone), the blisters are much more robust and tense compared to pemphigus vulgaris, where the split is intraepidermal and the blisters are flaccid.

Key Conceptual Distinction from Pemphigus

Pemphigus = intraepidermal split (acantholysis, flaccid blisters, Nikolsky +ve). Bullous pemphigoid = subepidermal split (no acantholysis, tense blisters, Nikolsky −ve). This is the single most important differentiating concept.

Most common form of autoimmune blistering disease ^[1]^[3] — this is universally true and highly examinable.
Incidence: approximately 4–22 per million per year (uncommon overall but the commonest in its category) ^[2].
Age: most cases occur in patients > 50 years old, with a median age of ~80 years ^[1]^[2]. The incidence rises sharply with age; BP is overwhelmingly a disease of the elderly.
Sex: slight female preponderance (M:F ≈ 1:1.2–1.5) ^[2].
More prevalent in elderly patients with neurological disease — including stroke, dementia, Parkinson's disease ^[1]^[2]. This association is striking and likely relates to the fact that BP180 and BP230 are also expressed in central nervous system neurons; shared antigenic targets may drive cross-reactivity.
Geographic variation: incidence appears to be rising globally, partly due to ageing populations and increased use of implicated drugs.

High Yield: In a geriatric patient with neurological comorbidities who develops pruritic urticarial lesions progressing to tense bullae — think BP immediately.

3. Anatomy and Function of the Dermal–Epidermal Junction

Understanding the target structure is crucial to understanding the disease.

The BMZ is the interface between the epidermis (above) and the dermis (below). Moving from the basal keratinocyte downward, the layers are:

Basal keratinocyte cell membrane — contains hemidesmosomes (anchoring junctions that attach basal keratinocytes to the underlying basement membrane)
Lamina lucida — the electron-lucent zone just beneath the cell membrane
Lamina densa — the electron-dense zone; the "core" of the basement membrane, composed primarily of type IV collagen
Sub-lamina densa / anchoring fibrils — composed of type VII collagen, anchoring the basement membrane into the papillary dermis

Hemidesmosomes are multi-protein complexes that anchor basal keratinocytes to the basement membrane. Key molecular components:

Component	Location	Role	Relevance
BP230 (BPAg1)	Intracellular (plaque of hemidesmosome)	Links intermediate filaments (keratin) to the hemidesmosome plaque	Target of anti-BP230 IgG in BP
BP180 (BPAg2 / type XVII collagen)	Transmembrane (extends from intracellular plaque through cell membrane into lamina lucida)	Structural transmembrane anchor	Primary pathogenic target — the NC16A domain of BP180 is the immunodominant epitope
Integrin α6β4	Transmembrane	Links to laminin-332 below	Mutated in junctional epidermolysis bullosa
Plectin	Intracellular	Connects cytoskeleton to hemidesmosome	Mutated in EB simplex with muscular dystrophy
Laminin-332 (laminin-5)	Lamina lucida	Bridges hemidesmosome to lamina densa	Target in mucous membrane pemphigoid

Hemidesmosomes maintain epidermal–dermal adhesion. When autoantibodies destroy or disrupt these junctions, the epidermis separates from the dermis at the lamina lucida level → subepidermal blister.

Why are BP blisters tense?

Because the entire epidermis forms the blister roof. The full-thickness epidermis is a much stronger "lid" than the thin suprabasal roof in pemphigus, so BP blisters remain intact longer and are under tension. In contrast, pemphigus blisters are flaccid because only the upper epidermis (above the acantholytic split) forms the roof.

4. Aetiology and Risk Factors

BP is fundamentally an autoimmune disease mediated by IgG autoantibodies against BP180 and BP230. The trigger for loss of self-tolerance is often unclear, but several contributing factors are recognised:

Category	Details	Mechanism
Age	> 60 years, median ~80y	Immunosenescence, cumulative antigen exposure
Neurological disease	Stroke, dementia, Parkinson's disease, multiple sclerosis ^[1]^[2]	BP180/BP230 are expressed in CNS neurons; neuronal damage may expose these antigens and trigger cross-reactive immune response ("epitope spreading")
Genetics	HLA-DQB10301* ^[2]	Predisposes to autoimmune recognition of BP antigens
Drugs (drug-associated BP)	PD-1 inhibitor immunotherapies (e.g. pembrolizumab), DPP-4 inhibitors ("gliptins") ^[1] — also loop diuretics (furosemide), penicillamine, antibiotics, NSAIDs	Immune checkpoint inhibitors release immune brakes → autoimmunity; DPP-4 inhibitors may alter epitope exposure on BP180; other drugs may cause molecular mimicry or direct antigenic alteration
Malignancy	Can be a trigger ^[1]	Paraneoplastic mechanism; unclear whether truly increased incidence or ascertainment bias; routine age-appropriate cancer screening recommended
Infections	Can be a trigger ^[1]	Molecular mimicry; cross-reactivity between microbial antigens and BP180
Immobility / institutionalisation	Bed-bound, old-age home residents ^[3]	Possibly friction/trauma exposing dermal antigens ("Koebnerisation") + infection risk

High Yield: Drug-Associated BP

PD-1 inhibitors (e.g. pembrolizumab) and DPP-4 inhibitors (gliptins — e.g. sitagliptin, vildagliptin, linagliptin) are the two most important drug classes to remember as triggers of BP ^[1]. In a diabetic elderly patient on a gliptin who develops blistering — always consider drug-associated BP.

Hong Kong has one of the most rapidly ageing populations in Asia → increasing incidence of BP
DPP-4 inhibitors are widely prescribed for type 2 diabetes (high prevalence) → drug-associated BP is an increasingly recognised entity in HK
PD-1/PD-L1 inhibitors are used in lung cancer (very common in HK/China), melanoma, head and neck cancers → checkpoint inhibitor-associated BP is emerging
High prevalence of hepatitis B in HK has limited relevance to BP specifically, but immunosuppressive treatment of BP requires HBV screening (risk of reactivation)
Neurological diseases (stroke, Parkinson's, dementia) are common in the HK elderly population → be alert for BP in this cohort

5. Pathophysiology

The pathophysiology of BP can be broken down into a logical cascade:

Through a combination of genetic susceptibility (HLA-DQB1*0301), age-related immune dysregulation, and environmental triggers (drugs, infections, neuronal damage), autoreactive B cells produce IgG autoantibodies against BP180 (specifically the NC16A ectodomain) and BP230 ^[2].

IgG antibodies bind to the extracellular domain of BP180 and to BP230 at the hemidesmosomal complex in the basement membrane zone (BMZ). This binding occurs at the dermal–epidermal junction.

Antibody binding activates the classical complement pathway → generation of C3a and C5a (anaphylatoxins) → recruitment of inflammatory cells (neutrophils, eosinophils, mast cells) to the BMZ ^[2].

Eosinophils are particularly prominent in BP (hence peripheral eosinophilia is often seen)
Neutrophils and mast cells are also recruited
These cells release proteolytic enzymes (matrix metalloproteinases, elastase, mast cell tryptase) that directly damage the BMZ structural proteins and degrade hemidesmosomal attachments

The combined effect of:

Direct interference with hemidesmosomal adhesion (by autoantibody binding)
Complement-mediated inflammation
Protease-mediated destruction of BMZ components

→ Loss of dermal–epidermal adhesion → subepidermal cleavage at the lamina lucida level → formation of tense blisters with the full-thickness epidermis as the roof.

Why eosinophilia in BP?

Eosinophils are recruited to the BMZ by complement-derived chemotactic factors (C5a) and by Th2-mediated cytokines (IL-5, eotaxin). Once at the BMZ, eosinophils degranulate and release major basic protein and eosinophil cationic protein, which further damage the BMZ. This is why eosinophilia may be present in peripheral blood ^[3] and eosinophilic infiltrates are seen on histology.

6. Classification

BP has a characteristic biphasic clinical course that is critical to recognise:

Phase	Features	Pitfall
Pre-bullous (prodromal) phase	Pruritus, eczematous, papular, or urticaria-like lesions ^[2]^[3] — may last weeks to months	Very non-specific; can be missed easily ^[3]. Often misdiagnosed as eczema, urticaria, drug eruption, or contact dermatitis
Bullous phase	Classic tense bullae on erythematous/urticarial base	Diagnostic — but may still be confused with other blistering conditions

Must Recognise Early Signs

Must recognise early signs of bullous pemphigoid → appears eczematous beforehand, very non-specific and can be missed ^[3]. A key clue: urticaria lasting > 24 hours should raise suspicion. In true urticaria, individual wheals resolve within 24 hours. If "urticarial" lesions persist > 24 hours, consider BP (or urticarial vasculitis) ^[3].

Variant	Features
Generalised BP (classic)	Widespread tense bullae on erythematous base; most common presentation
Localised BP (up to 30%)	Blisters confined to one area (e.g. pretibial, perilesional, vulvar) ^[2]
Pre-bullous / non-bullous BP	Only pruritus, urticarial plaques, or eczematous lesions without frank blisters — atypical case with no intact blisters ^[3]
Vesicular BP	Small vesicles rather than large bullae
Vegetating BP	Vegetating (heaped-up) plaques, especially in intertriginous areas
Dyshidrosiform BP	Mimics dyshidrotic eczema with vesicles on palms/soles
Erythrodermic BP	Generalised erythema with blistering
Drug-induced BP	Associated with DPP-4 inhibitors, PD-1 inhibitors, etc. — may resolve with drug withdrawal
Childhood BP	Rare; often involves genital and acral areas

Feature	Bullous Pemphigoid	Pemphigus Vulgaris	Dermatitis Herpetiformis	Linear IgA Disease
Level of split	Subepidermal (lamina lucida)	Intraepidermal (suprabasal)	Subepidermal	Subepidermal
Blister type	Tense	Flaccid	Grouped vesicles	Tense vesicles
Nikolsky sign	Negative	Positive	Negative	Negative
Target antigen	BP180, BP230	Desmoglein 1, 3	Tissue transglutaminase / epidermal TG	LAD-1 (BP180 fragment)
Predominant Ig	IgG	IgG	IgA	IgA
DIF pattern	Linear IgG and C3 at DEJ	Intercellular ("fishnet") IgG	Granular IgA at dermal papillae	Linear IgA at DEJ
Mucosal involvement	10–30% (most commonly oral)	Almost 100%	Rare	Common
Age	Elderly (> 60y)	Middle-aged (40–60y)	Young adults	Any age (bimodal)
Association	Neurological disease	—	Coeliac disease	Drugs (vancomycin)

7. Clinical Features

Symptom	Pathophysiological Basis
Severe pruritus (often the earliest and most prominent symptom)	Eosinophilic and mast cell degranulation at the BMZ → release of histamine, leukotrienes, and eosinophil-derived pruritogenic mediators; pruritoceptive C-fibres are stimulated
Burning or stinging sensation at skin lesion sites	Local inflammation (complement activation, cytokine release) at the DEJ irritates superficial cutaneous nerves
Oral discomfort (in 10–30% with mucosal involvement)	Erosions on oral mucosa are painful, exacerbated by eating/drinking; less severe than pemphigus vulgaris (which almost always has mucosal involvement)
Malaise / reduced oral intake (in severe disease)	Extensive skin involvement → fluid/protein loss; mucosal erosions → difficulty eating

Pruritus as the Key Symptom

In an elderly patient with intense, unexplained pruritus — even without visible blisters — always consider pre-bullous BP. Excoriation = must be itchy condition ^[3]. The pre-bullous phase can be the sole presentation for weeks to months.

7.2 Signs

Sign	Description	Pathophysiological Basis
Urticarial plaques	Fixed, erythematous, oedematous plaques that do not resolve within 24 hours ^[3]	Early complement-mediated inflammation and eosinophilic infiltration at the BMZ → persistent dermal oedema (unlike true urticaria where mast cell-mediated oedema resolves in < 24h because it is driven by transient mediator release)
Eczematous patches	Erythematous, scaly, sometimes excoriated patches mimicking eczema	Low-grade inflammation at the BMZ without sufficient damage to cause frank blistering
Excoriations	Linear scratch marks	Response to intense pruritus
Pre-bullous urticarial papules ^[3]	Small raised papules on an urticarial base	Early focal BMZ inflammation

Sign	Description	Pathophysiological Basis
Tense, intact bullae (1–3 cm)	Classically tense bulla on an erythematous, urticarial base ^[2]	Subepidermal split → full-thickness epidermis forms a thick, robust blister roof; fluid accumulates under pressure in the blister cavity
Erythematous / urticarial base surrounding blisters	Red, oedematous skin around the bulla	Base of blisters is also erythematous in BP ^[3] — due to complement-mediated vasodilation and inflammatory cell infiltrate in the papillary dermis
Serous or haemorrhagic blister fluid	Clear (serous) or blood-tinged fluid within the bulla	Inflammatory exudate ± capillary damage from protease release; haemorrhagic fluid suggests more severe inflammation
Erosions and crusts (after blister rupture)	Moist, denuded areas with overlying crust	Once the tense blister eventually ruptures (mechanically or from disease progression), the denuded dermis is exposed; erosions resolve without scarring because the basement membrane and dermis are otherwise intact ^[2]
Nikolsky sign NEGATIVE	Lateral pressure on perilesional skin does NOT cause epidermal separation	Because the epidermis itself is intact — the split is at the DEJ, not within the epidermis. In pemphigus, the intraepidermal acantholysis allows lateral shearing
Mucosal erosions (10–30%)	Most commonly oral cavity; may also involve conjunctiva, nose, genitalia	Mucosal basement membrane has similar BP180/230 expression but mucosal involvement is less common than in pemphigus (because desmoglein compensation theory does not apply here; it is more about the relative density of hemidesmosomal antigen expression)

Oral erosions possible in bullous pemphigoid → 17% of patients of BP will have oral mucosal erosions ^[3]

Commonly trunk, extremity flexures, axillary and inguinal areas ^[2]
Lower abdomen, inner thighs, forearms
Blisters over palms are usually tense, since the skin is thickest here ^[3]
Blisters over the arms are less tense and ruptured, since skin is thinner ^[3]
Can be localised (pretibial, vulvar, etc.) in up to 30% of cases

Clinical Pearl	Explanation
Urticaria > 24 hours → think BP ^[3]	True urticaria: individual wheals resolve < 24h. Persistent wheals → consider BP or urticarial vasculitis
Erythematous base helps differentiate BP from oedema blisters ^[3]	Oedema blisters in LL (from cirrhosis, CHF) can mimic BP — check for surrounding erythema ^[3]. Oedema blisters arise from hydrostatic pressure in dependent areas and lack the inflammatory erythematous base
Eosinophilia may be present ^[3]	Peripheral blood eosinophilia reflects the eosinophilic-predominant inflammation; supports diagnosis but is not specific
Require needle puncture to relieve tension of blister, but do not de-roof the blister ^[3]	The blister roof (intact epidermis) acts as a biological dressing → de-roofing exposes the denuded dermis and increases infection risk
BP180 may correlate with disease activity ^[3]	Anti-BP180 ELISA titres can be used to monitor response to treatment (higher titre = more active disease), though not universally available
Superimposed infection (HSV, MRSA) should be suspected when erosions fail to heal	Suspect when all other erosions are healed, apart from one patch ^[3] — always swab non-healing erosions for viral PCR and bacterial culture

Chronic, relapsing-remitting ^[2]
Self-limiting in some patients (may remit within months to years, but relapses are common)
Mortality is significant in the elderly population — not from the blisters themselves but from complications of treatment (immunosuppression → infection) and comorbidities (frailty, immobility, neurological disease)
1-year mortality: approximately 20–40% in elderly cohorts (largely reflecting baseline comorbidity burden)

Association	Notes
Neurological disease	Stroke, dementia, Parkinson's disease, mood disorders ^[1]^[2] — bidirectional association; BP180/230 expressed in CNS
Malignancy	Trigger for BP ^[1]; debated whether truly increased risk vs. age-related coincidence; age-appropriate screening recommended
Drug exposure	DPP-4 inhibitors, PD-1 inhibitors ^[1], diuretics, antibiotics
Diabetes mellitus	High comorbidity prevalence in the elderly; also relevant because of gliptin use
Other autoimmune diseases	Occasionally co-occurs with other autoimmune conditions

High Yield Summary

Bullous Pemphigoid — Key Points for Exams:

Most common autoimmune blistering disease; predominantly affects elderly (> 60y, median ~80y)
Autoantibodies against BP180 (NC16A domain) and BP230 at hemidesmosomes → subepidermal split → tense bullae
Tense blisters on an erythematous, urticarial base (cf. pemphigus = flaccid blisters)
Nikolsky sign NEGATIVE (epidermis intact; split is at DEJ)
Pre-bullous phase mimics eczema or urticaria — suspect BP if urticaria > 24 hours
Associated with neurological disease (stroke, dementia, Parkinson's) — BP180/230 expressed in CNS
Drug triggers: DPP-4 inhibitors (gliptins) and PD-1 inhibitors (pembrolizumab)
Mucosal involvement in ~10–30% (usually oral; less prominent than pemphigus)
Eosinophilia may be present; eosinophilic infiltrate is characteristic histologically
Diagnosis: perilesional biopsy → H&E (subepidermal split) + Direct IF (linear IgG and C3 at DEJ) + Serology (anti-BP180/BP230 ELISA)
Blister roof should NOT be de-roofed — puncture only to relieve tension
Erythematous base distinguishes BP from oedema blisters (CHF, cirrhosis)
First-line treatment: tetracyclines (for mild-moderate) or topical/systemic corticosteroids; topical steroids may be better than oral steroids (NEJM evidence)

Active Recall - Bullous Pemphigoid (Definition, Epidemiology, Pathophysiology, Clinical Features)

^[1] Lecture slides: CFB (MED09) Dermatology (II).pdf, p9 ^[2] Senior notes: Ryan Ho Rheumatology.pdf, p152–153 ^[3] Senior notes: Block A - Dermatology PBL 2.pdf, p3–4

Differential Diagnosis of Bullous Pemphigoid

The differential diagnosis of BP depends critically on the phase of presentation. The pre-bullous phase is a diagnostic minefield because there are no blisters — just itchy, urticarial, or eczematous lesions. The bullous phase narrows the field to other blistering conditions but still requires careful distinction. Below, I organise differentials by clinical scenario, explain why each mimics BP, and detail the key distinguishing features.

When approaching a patient with suspected BP, ask yourself two questions first:

Is there blistering? → If yes, differential is "other causes of cutaneous blisters." If no, differential is "causes of pruritus / urticaria / eczematous eruptions in the elderly."
What level is the split? → Subepidermal (tense blisters, Nikolsky −ve) vs. intraepidermal (flaccid blisters, Nikolsky +ve) vs. no split (non-blistering).

Important to exclude other autoimmune blistering skin diseases and drug cause ^[1]. May present with variable features weeks before blisters appear, e.g. urticarial-like red skin ^[1].

The GC 2026 lecture slides explicitly list the differentials in two clinical contexts ^[4]:

For a blistering erosive presentation: Pemphigus vulgaris / Stevens-Johnson syndrome / Toxic epidermal necrolysis / Bullous pemphigoid / Paraneoplastic pemphigus
For a tense bullae presentation: Bullous pemphigoid, contact dermatitis, insect bite reactions, epidermolysis bullosa acquisita

2. Differential Diagnosis by Phase

These are the conditions that mimic the pre-bullous urticarial / eczematous phase ^[3]^[5].

Differential	Why It Mimics BP	Key Distinguishing Features
Chronic spontaneous urticaria	Itchy wheals on the trunk/limbs in an elderly patient — looks identical to pre-bullous BP urticarial plaques	Individual wheals in true urticaria resolve within 24 hours ^[3]^[5]; in BP, urticarial plaques are fixed and persist > 24h. Mark a wheal with a pen — if it is still there the next day, suspect BP or urticarial vasculitis
Urticarial vasculitis ^[3]^[5]	Also presents with urticarial lesions that persist > 24 hours	Urticarial vasculitis lesions are often painful/burning (rather than purely pruritic), may leave purpura or post-inflammatory hyperpigmentation after resolution, and biopsy shows leukocytoclastic vasculitis with fibrinoid necrosis of vessel walls — not subepidermal cleavage. May be associated with hypocomplementaemia (anti-C1q antibodies in hypocomplementaemic urticarial vasculitis syndrome)
Eczema / atopic dermatitis	Pruritic, erythematous, scaly patches — the eczematous variant of pre-bullous BP is easily misdiagnosed as eczema	Eczema typically has a chronic relapsing history, flexural distribution in adults, personal/family atopic history. BP eczematous lesions often affect non-typical sites (trunk, limbs) and are refractory to standard eczema treatment. Key: if "eczema" in an elderly patient fails to respond to emollients and topical steroids, biopsy to exclude BP
Drug eruption ^[6]	Widespread morbilliform or urticarial rash in an elderly patient on multiple medications	Temporal relationship to drug introduction, widespread morbilliform pattern, involvement of trunk → extremities, usually resolves after drug withdrawal. BP drug triggers (gliptins, PD-1 inhibitors) can blur this distinction — in drug-associated BP, the eruption persists after stopping non-implicated drugs
Viral exanthem ^[6]	Diffuse macular/papular rash, sometimes urticarial	Usually febrile, shorter duration, symmetrical, self-limiting; serology/PCR can identify viral cause
Bites / papular urticaria ^[4]^[6]	Grouped itchy papules or small vesicles on exposed areas	History of exposure, grouped/linear pattern ("breakfast-lunch-dinner" clustering), predilection for exposed skin, seasonal variation. Central punctum may be visible. Biopsy shows wedge-shaped eosinophilic infiltrate without linear IgG at DEJ
Scabies	Intensely pruritic papules and excoriations in an elderly patient, especially in institutions (old-age homes)	Burrows in web spaces, wrists, genitalia; nocturnal pruritus worse; close contacts affected; dermoscopy shows mite/eggs; KOH scraping diagnostic
Dermatitis herpetiformis (pre-vesicular)	Extremely itchy papules, often excoriated before vesicles form	Younger patients (20–40y), extensor distribution (elbows, knees, buttocks), associated with coeliac disease, granular IgA at dermal papillae on DIF (not linear IgG at DEJ)

The Urticaria > 24 Hours Rule

Urticaria > 24 hours should trigger two differential diagnoses: bullous pemphigoid and urticarial vasculitis ^[3]^[5]. This is a clinical pearl that appears repeatedly in HKUMed dermatology teaching. Always mark the wheals and review at 24 hours.

Once frank blisters develop, the differential narrows. The key organising principle is the level of the split and the character of the blister ^[2].

Differential	Level of Split	Blister Character	Key Distinguishing Features
Pemphigus vulgaris ^[4]	Intraepidermal (suprabasal)	Flaccid blisters that rupture easily → painful erosions	Younger patients (40–60y); Nikolsky sign +ve; mucosal involvement in almost all patients (oral erosions are the presenting feature in ~50–70%); DIF shows intercellular IgG ("chicken-wire/fishnet pattern") throughout epidermis; serology: anti-desmoglein 1/3 ^[2]^[7]
Pemphigus foliaceus	Intraepidermal (subcorneal)	Very superficial — often only erosions/crusts, NO intact blisters	Cutaneous only (no mucosal involvement); "corn flake"-like scale-crusts; DIF: intercellular IgG in upper epidermis; serology: anti-desmoglein 1 only
Stevens-Johnson syndrome / Toxic epidermal necrolysis ^[4]	Subepidermal (full-thickness epidermal necrosis)	Flaccid blisters + widespread epidermal detachment; Nikolsky +ve	Drug history (allopurinol, AEDs, sulfonamides); acutely unwell with high fever, mucosal involvement (oral, ocular, genital); skin detachment > 30% BSA in TEN; histology shows full-thickness epidermal necrosis (not just subepidermal cleavage with eosinophils); high mortality
Contact dermatitis (bullous) ^[4]	Intraepidermal (spongiotic)	Small vesicles to occasional bullae at contact site	Distribution corresponds to contactant exposure (hands, face); history of exposure; patch testing positive; histology shows spongiosis without linear IgG at DEJ
Insect bite reactions ^[4]	Subepidermal	Tense vesicles/bullae at bite sites — can look identical to BP!	Grouped lesions on exposed areas; central punctum; history of exposure; limited in distribution; biopsy shows wedge-shaped perivascular infiltrate with eosinophils but no linear IgG/C3 at DEJ on DIF
Epidermolysis bullosa acquisita (EBA) ^[4]	Subepidermal (sub-lamina densa)	Tense bullae, often acral, heal with scarring and milia	Skin fragility predominantly on trauma-prone sites (hands, feet, elbows, knees); heals with scarring and milia (BP heals without scarring); associated with IBD; DIF shows linear IgG at DEJ but salt-split skin localises to the dermal side (floor) — cf. BP where it is on the epidermal side (roof)
Paraneoplastic pemphigus ^[4]	Intraepidermal + interface dermatitis	Polymorphous — blisters, erosions, lichenoid lesions	Severe stomatitis (more painful and refractory than PV); associated with haematological malignancy (lymphoma, CLL, Castleman disease); anti-envoplakin and periplakin antibodies; poor prognosis
Bullous drug eruption	Variable	Tense or flaccid blisters	Drug temporal relationship; may be morphologically identical to BP (drug-induced BP) or present as fixed drug eruption (target-like, recurs at same site); biopsy and DIF help distinguish
Linear IgA bullous dermatosis	Subepidermal	Tense vesicles/bullae, often in "string of pearls" arrangement	Can be drug-induced (classically vancomycin); DIF shows linear IgA (not IgG) at DEJ — this is the distinguishing feature; may have mucosal involvement
Dermatitis herpetiformis	Subepidermal	Grouped vesicles on extensor surfaces	Younger patients; extensor distribution (elbows, knees, buttocks); intensely pruritic; associated with coeliac disease (anti-tTG IgA positive); DIF shows granular IgA at dermal papillae
Porphyria cutanea tarda	Subepidermal	Tense blisters on sun-exposed (photodistributed) areas — dorsal hands, forearms, face	Photodistribution; skin fragility; hypertrichosis; elevated urine/plasma porphyrins; associated with alcohol, HCV, iron overload; DIF may show IgG at DEJ (can mimic BP) but porphyrin studies are diagnostic
Oedema blisters (stasis blisters) ^[3]	Subepidermal	Tense blisters on dependent lower limbs	Can mimic BP ^[3]; arise from hydrostatic pressure in patients with CHF, cirrhosis, or nephrotic syndrome; lack surrounding erythema (BP has erythematous base) ^[3]; bilateral pitting oedema; no eosinophils on biopsy; DIF negative
Bullosis diabeticorum	Subepidermal	Spontaneous painless tense blisters on lower legs/feet	Diabetic patients; acral distribution; spontaneous; self-limiting; DIF usually negative

Oedema Blisters vs BP — A Common Clinical Confusion

Oedema blisters in the lower limbs (from cirrhosis, CHF) can mimic BP, so you have to see if there is any surrounding erythema ^[3]. The base of blisters is erythematous in BP ^[3] — this surrounding erythema is the key distinguishing feature. Oedema blisters sit on oedematous, non-inflamed skin.

The following systematic approach helps narrow the differential in a patient presenting with cutaneous blisters:

While full investigations will be covered in the next section, the differentials are best resolved by:

Investigation	What It Resolves
Skin biopsy for H&E	Level of split (subepidermal vs. intraepidermal); inflammatory infiltrate pattern (eosinophils in BP vs. neutrophils in DH/linear IgA vs. acantholysis in pemphigus)
Direct immunofluorescence (DIF) — perilesional biopsy	Linear IgG/C3 along BMZ ^[1] = BP; intercellular IgG = pemphigus; linear IgA = linear IgA disease; granular IgA = DH; negative = non-immunobullous
Salt-split skin technique	Differentiates BP (IgG on epidermal/roof side) from EBA (IgG on dermal/floor side) — both show linear IgG at DEJ on standard DIF
Anti-skin antibody + specific ELISA	Anti-BP180/BP230 ^[1]^[4] = BP; anti-desmoglein 1/3 = pemphigus; anti-envoplakin/periplakin = paraneoplastic pemphigus
Drug history review	Important to rule out drug-induced BP ^[1]; also distinguishes SJS/TEN, fixed drug eruption, linear IgA disease (vancomycin)

Important to rule out other autoimmune/drug-induced BP ^[1]

Feature	Bullous Pemphigoid	Pemphigus Vulgaris	SJS/TEN	EBA	Linear IgA Disease
Age	> 60y (median 80)	40–60y	Any age	Adults	Bimodal (children + adults)
Blister	Tense	Flaccid	Flaccid + sheet-like detachment	Tense, acral	Tense, "string of pearls"
Nikolsky	−ve	+ve	+ve	−ve	−ve
Mucosal	10–30%	~100%	Extensive (oral, ocular, genital)	Common	Common
Scarring	No	No	Yes (if severe)	Yes + milia	No
DIF	Linear IgG/C3 DEJ	Intercellular IgG	Non-specific necrosis	Linear IgG DEJ (dermal side)	Linear IgA DEJ
Target Ag	BP180, BP230	Dsg 1, 3	N/A (drug-mediated keratinocyte apoptosis)	Type VII collagen	LAD-1 (BP180 fragment)
Key association	Neuro disease, gliptins	—	Drugs (allopurinol, AEDs)	IBD	Vancomycin

For completeness, the comprehensive differential of blisters by distribution is worth knowing:

Distribution	Differential Diagnoses
Generalised with systemic illness	SJS/TEN, varicella zoster, staphylococcal scalded skin syndrome, disseminated HSV, Sweet syndrome, paraneoplastic pemphigus
Isolated generalised	Pemphigus, bullous pemphigoid, pemphigoid gestationis, dermatitis herpetiformis, EBA, bullous impetigo (neonates)
Dependent areas	Oedema/stasis blisters, bullous vasculitis, bullosis diabeticorum
Hands/feet	Pompholyx, tinea, friction blisters, erythema multiforme, localised EB simplex
Photodistributed	Sunburn/phototoxic reactions, PMLE, porphyria cutanea tarda, pseudoporphyria
Dermatomal	Herpes zoster
Linear	Contact dermatitis, phytophotodermatitis
Mucosal involvement	Pemphigus vulgaris (majority), pemphigoid (some), herpes simplex, EM, SJS/TEN

High Yield Summary — Differential Diagnosis of Bullous Pemphigoid

Pre-bullous phase DDx: urticaria (resolves < 24h), urticarial vasculitis (painful, purpura, persists > 24h), eczema, drug eruption, viral exanthem, bites/papular urticaria, scabies
Bullous phase DDx (tense blisters): BP, contact dermatitis, insect bite reactions, epidermolysis bullosa acquisita ^[4]
Bullous phase DDx (flaccid blisters/erosions): pemphigus vulgaris, SJS/TEN, paraneoplastic pemphigus ^[4]
Key distinguishing features of BP: tense blisters, Nikolsky −ve, erythematous base, heals without scarring, linear IgG/C3 at DEJ on DIF, anti-BP180/230
Oedema blisters (CHF/cirrhosis) mimic BP — differentiate by absence of surrounding erythema ^[3]
EBA mimics BP on standard DIF — differentiate by salt-split skin (EBA = dermal floor; BP = epidermal roof) and clinical features (EBA scars with milia, acral)
Always rule out drug-induced BP — especially DPP-4 inhibitors and PD-1 inhibitors ^[1]

Active Recall - Differential Diagnosis of Bullous Pemphigoid

References

^[1] Lecture slides: CFB (MED09) Dermatology (II).pdf, p9–10 ^[2] Senior notes: Ryan Ho Rheumatology.pdf, p147–148, p153 ^[3] Senior notes: Block A - Dermatology PBL 2.pdf, p3–4 ^[4] Lecture slides: Derm General Clerkship 2026 Part2.pdf, p2, p18 ^[5] Senior notes: Block A - It is red and painful (bacterial and viral skin infections).pdf, p24 ^[6] Lecture slides: Dermatology I by Dr Chan.pdf, p17 ^[7] Senior notes: Maksim Medicine Notes.pdf, p71

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for Bullous Pemphigoid

Unlike many medical conditions, bullous pemphigoid does not have a single universally adopted "diagnostic criteria checklist" akin to the Jones criteria for rheumatic fever. Instead, diagnosis is by clinical features, confirmed with skin biopsy and serology ^[1]. In practice, a confident diagnosis of BP requires concordance across three pillars:

Pillar	What It Provides	Essential?
1. Clinical	Compatible clinical picture (tense bullae ± urticarial base ± pruritus in an elderly patient)	Yes — raises the suspicion
2. Histopathology (H&E)	Subepidermal blister with characteristic inflammatory infiltrate	Supportive — shows the level of split
3. Immunopathology (Direct IF)	Linear IgG/C3 along BMZ ^[1]^[4] — the gold standard confirmatory test	Essential — confirms autoimmune aetiology

A fourth supportive element is serology (anti-BP180/BP230 antibodies), which can further corroborate the diagnosis and be used for monitoring.

The Gold Standard for Diagnosis

Skin biopsy for direct immunofluorescence (DIF) showing linear IgG/C3 deposits along the basement membrane zone is the gold standard for diagnosing BP ^[1]^[4]^[7]. H&E histology alone is supportive but not sufficient — many subepidermal blistering diseases look similar on light microscopy. It is the DIF pattern that clinches the diagnosis.

Practical Diagnostic Framework (Consensus Approach)

A diagnosis of BP can be made when all three of the following are met:

Clinical: ≥ 1 of the following:
- Tense bullae on an erythematous/urticarial base (classic)
- Pruritic urticarial/eczematous lesions persisting > 24 hours (pre-bullous)
- Erosions in an elderly patient with no intact blisters (atypical)
Histology: Subepidermal cleft/blister with dermal neutrophil ± eosinophil infiltrates ^[1]
Immunopathology: Linear IgG and/or C3 along the DEJ on direct IF ^[1]^[4]

Supportive criteria (not required but strengthen the diagnosis):

Positive anti-skin antibody titre at the DEJ ^[1]^[3]
Positive anti-BP180 and/or anti-BP230 ELISA ^[1]^[4]
Peripheral blood eosinophilia ^[3]

The following algorithm outlines the systematic approach from clinical suspicion to confirmed diagnosis:

Two Biopsies, Two Purposes

Always take two biopsies from different sites: (1) A biopsy from lesional skin (edge of a fresh blister, including perilesional skin) for H&E histology — this shows the level of split and inflammatory infiltrate. (2) A biopsy from perilesional, uninvolved skin (normal-appearing skin ~1 cm from a lesion) for direct IF — this detects immune deposits. If you biopsy a blister for DIF, the inflammation may destroy the immune deposits and give a false negative.

3. Investigation Modalities — Detailed Breakdown

Test	Method	Interpretation in BP
Nikolsky sign	Apply lateral sliding pressure with a finger on normal-appearing perilesional skin	Negative in BP (epidermis does not shear off because the intraepidermal adhesion is intact — the split is subepidermal). Positive in pemphigus and SJS/TEN
Blister character	Inspect: tense vs. flaccid, intact vs. ruptured, surrounding skin	Tense, intact bullae on erythematous/urticarial base = classic BP. Flaccid = think pemphigus. Erythematous base helps differentiate from oedema blisters ^[3]
Wheal persistence	Mark an urticarial lesion with a skin marker pen, reassess at 24 hours	Wheal present at same site after 24h → NOT simple urticaria → consider BP or urticarial vasculitis ^[3]^[5]

The GC 2026 lecture explicitly lists the following blood workup ^[4]:

CBC, LRFT, fasting glucose, HbA1c, HBsAg, anti-HBc, anti-skin antibody, anti-BP180, anti-BP230 ELISA ^[4]

Investigation	Rationale	Expected Findings in BP
CBC with differential ^[4]	Screen for eosinophilia; baseline before immunosuppressive therapy	Eosinophilia may be present ^[3] — reflects the eosinophilic nature of the inflammatory infiltrate. Not specific but supportive
LRFT ^[4]	Baseline renal and liver function before starting steroids/immunosuppressants; exclude uraemic pruritus as alternative diagnosis	Usually normal (unless comorbidities). LFT important for azathioprine/methotrexate dosing
Fasting glucose, HbA1c ^[4]	Screen for diabetes (common in elderly; relevant for steroid use and DPP-4 inhibitor-associated BP)	May reveal undiagnosed DM; HbA1c important for monitoring steroid-induced hyperglycaemia
HBsAg, anti-HBc ^[4]	Pre-immunosuppression hepatitis B screening — immunosuppressive agents (steroids, rituximab, azathioprine) can cause HBV reactivation	If HBsAg+ or anti-HBc+ → check HBV DNA → start antiviral prophylaxis before immunosuppression. This is critical in Hong Kong where HBV prevalence is ~7–8%
Anti-skin antibody titre (indirect IF at DEJ) ^[1]^[3]^[4]	Detects circulating IgG antibodies that bind the DEJ	+ve anti-skin antibody at DEJ ^[3] supports BP. Sensitivity ~70–80%. Titre may correlate with disease activity
Anti-BP180 ELISA ^[1]^[4]	Detects IgG against the NC16A domain of BP180 — the immunodominant epitope	Sensitivity ~85–90%, specificity ~95–98%. BP180 may correlate with disease activity ^[3] — useful for monitoring treatment response. Higher titres → more active disease
Anti-BP230 ELISA ^[1]^[4]	Detects IgG against BP230 (intracellular hemidesmosomal antigen)	Less sensitive than anti-BP180 (~60–70%); less useful for monitoring. Some patients are BP230-positive but BP180-negative (milder phenotype)

Anti-BP180 ELISA Availability

Anti-BP180 and anti-BP230 ELISA are not available at QMH (Queen Mary Hospital) ^[4]. This is a practical consideration for HKUMed students — in clinical practice at QMH, the diagnosis relies on anti-skin antibody (indirect IF) + skin biopsy (H&E + DIF). ELISA may be sent to reference labs if needed.

Investigation	When to Order	Rationale
G6PD level	Before starting dapsone (a potential steroid-sparing agent)	Dapsone causes oxidative haemolysis — contraindicated in G6PD deficiency. HK has high prevalence of G6PD deficiency (~4.5% in males)
IgG, IgA, IgM levels	If considering immunosuppressive therapy; or if clinical picture suggests overlap with another immunobullous disease	Baseline immune status; IgA levels specifically if considering linear IgA disease in the differential
Wound swab for aerobic culture, HSV/VZV PCR	If erosions are not healing or look atypical	Superimposed HSV1 + MRSA → suspect when all other erosions are healed, apart from one patch ^[3]

3.3 Skin Biopsy — The Diagnostic Cornerstone

Two biopsies should be taken:

Where to biopsy: Edge of a fresh, early blister (include blister edge + adjacent perilesional skin in the specimen so you can see the transition).

Why H&E?: To demonstrate the level of the split and the pattern of inflammatory infiltrate — this distinguishes subepidermal from intraepidermal blistering and guides the differential.

Key histological findings in BP ^[1]^[4]:

Feature	Description	Why?
Subepidermal blister ^[1]^[4]	Cleavage plane at the dermal–epidermal junction (lamina lucida level); intact epidermis forms the blister roof	Autoantibodies target hemidesmosomes at the DEJ → loss of adhesion at lamina lucida
Dermal neutrophil ± eosinophil infiltrates ^[1]	Mixed inflammatory infiltrate in the upper dermis, often with prominent eosinophils	Complement-mediated recruitment of eosinophils and neutrophils; eosinophils are particularly characteristic of BP
Eosinophils in the blister cavity and dermis ^[4]	Eosinophils visible within the blister fluid and in perivascular infiltrates	Eosinophilic inflammation is a hallmark; helps distinguish from linear IgA disease (predominantly neutrophilic) or DH (neutrophilic microabscesses at dermal papillae)
Intact epidermis as blister roof	No acantholysis; keratinocytes within the blister roof are cohesive	Confirms subepidermal (not intraepidermal) split; no acantholysis distinguishes from pemphigus

On histology: subepidermal blister, dermal neutrophil +/- eosinophil infiltrates ^[1]

Where to biopsy: Perilesional, clinically normal-appearing skin — approximately 1 cm away from an active lesion. This is crucial because within the lesion, inflammation may destroy immune deposits and give false negatives.

Why DIF?: To detect in-situ immune deposits (immunoglobulins and complement) at the tissue level. This is different from serology, which detects circulating antibodies.

How it works: The biopsy is snap-frozen (not formalin-fixed), sectioned, and incubated with fluorescent-labelled anti-human IgG, IgA, IgM, C3, and fibrinogen antibodies. Under ultraviolet microscopy, the pattern and location of fluorescence identifies the disease.

Key DIF findings in BP ^[1]^[4]:

Finding	Significance
Linear C3 (~100%) along the dermoepidermal junction ^[4]	Nearly universally present; C3 deposition reflects complement activation at the BMZ — the key pathogenic mechanism
Linear IgG (> 90%) along the dermoepidermal junction ^[4]	IgG autoantibodies bound to BP180/BP230 at the hemidesmosomes; this is the diagnostic hallmark
Continuous, linear pattern	Distinguishes from: intercellular/fishnet (pemphigus), granular (DH), linear IgA (linear IgA disease)

DIF Pattern Comparison — High Yield Table

Disease	DIF Pattern	Immunoglobulin	Location
Bullous Pemphigoid	Linear	IgG + C3	Along DEJ/BMZ
Pemphigus vulgaris	Intercellular ("fishnet"/"chicken wire")	IgG	Between keratinocytes throughout epidermis
Pemphigus foliaceus	Intercellular	IgG	Between keratinocytes, upper epidermis
Linear IgA disease	Linear	IgA	Along DEJ
Dermatitis herpetiformis	Granular	IgA	At dermal papillae tips
Epidermolysis bullosa acquisita	Linear	IgG	Along DEJ (dermal side on salt-split)
Lupus band test	Granular	IgG, IgM, IgA, C3	Along DEJ (lesional and non-lesional in SLE)

When needed: When DIF shows linear IgG at the DEJ, you need to distinguish BP from epidermolysis bullosa acquisita (EBA) — both show the same DIF pattern on standard testing.

How it works: The skin biopsy is incubated in 1M NaCl solution, which causes cleavage at the lamina lucida (the weakest point of the BMZ). This artificially splits the specimen into an epidermal roof and a dermal floor. DIF is then repeated:

Disease	IgG Location After Salt-Split
Bullous pemphigoid	IgG on the epidermal (roof) side — because BP180/BP230 are hemidesmosomal antigens that remain attached to the epidermis
Epidermolysis bullosa acquisita	IgG on the dermal (floor) side — because type VII collagen (the target in EBA) is below the lamina lucida in the sub-lamina densa/anchoring fibrils, which remain with the dermis

This is an elegant technique that exploits the anatomical position of the target antigens relative to the cleavage plane.

Test	Method	Findings in BP	Sensitivity / Specificity
Anti-skin antibody / Indirect IF ^[1]^[3]	Patient's serum incubated with a substrate epithelium (e.g. monkey oesophagus); fluorescent-labelled anti-human IgG applied; observe under UV	Circulating IgG that binds the BMZ in a linear pattern	Sensitivity ~70–80%; cannot distinguish BP from EBA without salt-split
Anti-BP180 ELISA ^[1]^[4]	ELISA using recombinant NC16A domain of BP180 as antigen	Elevated anti-BP180 IgG titre	Sensitivity ~85–90%, specificity ~95–98%; may correlate with disease activity ^[3] — useful for monitoring
Anti-BP230 ELISA ^[1]^[4]	ELISA using recombinant BP230 as antigen	Elevated anti-BP230 IgG titre	Sensitivity ~60–70%, specificity ~90%; less useful alone but supports diagnosis when positive

Key point: Specific autoantibodies: BP180/BP230 ^[1]. These are more specific than indirect IF, and anti-BP180 levels may be used to monitor treatment response (rising titre suggests relapse, falling titre suggests remission).

Investigation	Indication	Rationale
CXR ^[4]	Baseline; if considering underlying malignancy or infection	Age-appropriate screening; baseline before immunosuppression
Age-appropriate cancer screening	All new BP patients	Malignancy can be a trigger ^[1]; screen with CXR, age-appropriate colonoscopy/mammography/PSA as indicated
Drug review	All patients	Important to rule out drug-induced BP ^[1] — systematically review for DPP-4 inhibitors (gliptins), PD-1 inhibitors, diuretics, antibiotics
Neurological assessment	If not already known	More prevalent in elderly patients with neurological disease ^[1] — document any history of stroke, dementia, Parkinson's disease
THSD1/CYP2C19 genotyping	Before starting certain medications (emerging)	Pharmacogenomic considerations for drug metabolism

Scenario-Based Interpretation

Scenario	Clinical	H&E	DIF	Serology	Diagnosis
Classic BP	Elderly, tense bullae, pruritus	Subepidermal blister, eosinophils	Linear IgG + C3 at DEJ	Anti-BP180 +ve	Confirmed BP
Pre-bullous BP	Elderly, urticarial plaques > 24h, no blisters	Eosinophilic spongiosis, no frank blister	Linear IgG + C3 at DEJ	Anti-BP180 +ve	Confirmed pre-bullous BP
Atypical BP — no intact blisters ^[3]	Elderly, excoriations, xerosis, pruritus only	May show subtle eosinophilic infiltrate	Anti-skin +ve at DEJ ^[3]	± positive	BP — atypical presentation
Linear IgA disease	Tense vesicles, "string of pearls"	Subepidermal blister, neutrophils	Linear IgA at DEJ	Anti-LAD-1	Linear IgA bullous dermatosis
EBA	Tense bullae, acral, scarring + milia	Subepidermal blister, pauci-inflammatory	Linear IgG at DEJ, dermal side on salt-split	Anti-type VII collagen	EBA
Oedema blisters	CHF/cirrhosis, bilateral LL oedema, no erythema	Subepidermal blister, pauci-inflammatory	Negative	Negative	Oedema blisters

The Atypical Presentation Trap

BP can present as an atypical case with no intact blisters ^[3] — only pruritus, excoriations, and xerosis. In Case 9 from PBL 2 ^[3], a 65-year-old female initially treated for uraemic pruritus was found to have anti-skin +ve at DEJ, confirming BP. The lesson: in elderly patients with refractory pruritus, always consider biopsy + DIF even without visible blisters.

Once diagnosis is confirmed, ongoing monitoring includes:

Parameter	Method	Interpretation
Clinical assessment	Count new blisters, extent of erosions, pruritus severity	Treatment aim: presence of 5–10 blisters once every 1–2 weeks ^[7] — this is the target indicating acceptable disease control
Anti-BP180 ELISA titre (if available)	Serial measurements	May correlate with disease activity ^[3] — rising titre suggests relapse; falling titre suggests treatment response
Peripheral eosinophil count	CBC with differential	May drop with successful treatment (less eosinophilic inflammation)
Secondary infection surveillance	Clinical assessment ± wound swab	Superimposed HSV1 + MRSA ^[3] — suspect when one patch of erosion refuses to heal

High Yield Summary — Investigations for Bullous Pemphigoid

Diagnosis is clinical, confirmed with skin biopsy and serology ^[1]
Two biopsies needed: lesional skin → H&E (subepidermal split + eosinophils); perilesional skin → DIF (linear IgG/C3 along BMZ — gold standard) ^[1]^[4]
Blood workup (GC 2026): CBC, LRFT, fasting glucose, HbA1c, HBsAg, anti-HBc, anti-skin antibody, anti-BP180, anti-BP230 ELISA ^[4]
DIF is the gold standard: linear C3 (~100%) and IgG (> 90%) along DEJ ^[4]
Salt-split skin: distinguishes BP (epidermal/roof side) from EBA (dermal/floor side)
Anti-BP180 ELISA: most sensitive and specific serological test; may correlate with disease activity ^[3]
Always rule out drug-induced BP and screen for HBV before immunosuppression ^[1]^[4]
Anti-BP180/BP230 ELISA not available at QMH ^[4] — rely on anti-skin antibody + DIF at QMH

Active Recall - Diagnosis and Investigations for Bullous Pemphigoid

References

^[1] Lecture slides: CFB (MED09) Dermatology (II).pdf, p9–10 ^[3] Senior notes: Block A - Dermatology PBL 2.pdf, p3–4 ^[4] Lecture slides: Derm General Clerkship 2026 Part2.pdf, p2, p18–19 ^[5] Senior notes: Block A - It is red and painful (bacterial and viral skin infections).pdf, p24 ^[7] Senior notes: Maksim Medicine Notes.pdf, p71 ^[8] Senior notes: Ryan Ho Rheumatology.pdf, p148, p153

Management of Bullous Pemphigoid

Managing BP in elderly, frail patients is a balancing act. The disease itself carries morbidity (pruritus, blistering, infection risk, fluid/protein loss), but the treatment — particularly systemic immunosuppression — carries its own mortality in this population. In fact, the leading cause of death in BP patients is not the blistering disease itself but complications of treatment (infection from immunosuppression, steroid side effects). This fundamentally shapes the approach:

Minimise systemic immunosuppression wherever possible
Topical corticosteroids are superior to oral corticosteroids for extensive BP — landmark NEJM evidence ^[3]^[4]
Tetracyclines are first-line in many dermatology centres as a steroid-sparing, anti-inflammatory option ^[9]
Withdraw offending drugs in drug-induced BP
Maintain meticulous wound care to prevent secondary infection

NEJM Evidence — Topical Better Than Oral

Topical clobetasol propionate cream (40 g per day) vs prednisone 1 mg/kg/day for extensive disease: topical corticosteroids were superior (p = 0.02). One-year survival rate was 76% in the topical-corticosteroid group and 58% in the oral-prednisone group ^[4]. This survival advantage is likely because topical steroids avoid the systemic side effects (infections, hyperglycaemia, osteoporosis, adrenal suppression) that kill frail elderly patients. But not feasible — 3 tubes a day, more than 1000 tubes per year ^[3] — so in practice, many patients with extensive disease end up needing systemic therapy due to impracticality of topical application.

3. Step-by-Step Management

These are universally applicable regardless of severity ^[1]^[7]:

Measure	Detail	Rationale
Blister care: prick but do NOT de-roof blisters ^[3]^[7]	Aspirate tense bullae with a sterile needle to prevent traumatic de-roofing ^[1]	The intact blister roof (full-thickness epidermis) acts as a biological dressing — it protects the underlying denuded dermis from desiccation and bacterial colonisation. De-roofing exposes a large raw surface → dramatically increases infection and fluid loss risk
Non-adhesive dressings ^[7]	Apply after aspiration	Adhesive dressings can inadvertently de-roof blisters when removed
Antiseptic solution for wound cleansing ^[1]	e.g. chlorhexidine, povidone-iodine washes for open erosions	Reduces bacterial colonisation of exposed dermis; prevents secondary infection
Maintain good oral and wound care ^[1]	Oral hygiene if mucosal involvement; soft diet; topical oral agents (e.g. Difflam mouthwash)	Oral erosions (present in ~17% of BP) cause pain with eating → malnutrition in elderly
Antibiotics if secondary bacterial infection ^[1]	Wound swab → targeted antibiotics; empirical anti-staphylococcal cover if clinical infection	Superimposed MRSA ^[3] is a recognised complication; infected erosions will not heal
HSV/VZV screen	Viral swab/PCR for non-healing erosions	Superimposed HSV1 ^[3] — suspect when all other erosions are healed apart from one persistent patch
Review and withdraw implicated drugs	Systematically review for diuretics, DPP-4 inhibitors (vildagliptin, linagliptin), immune checkpoint inhibitors (nivolumab, pembrolizumab), NSAIDs, antibiotics, ACE inhibitors, TNF inhibitors ^[4]	Drug-induced BP ^[4] may resolve or significantly improve after drug withdrawal. Always documented as a specific list

Drug-induced bullous pemphigoid — implicated drugs: diuretics, dipeptidyl peptidase-4 inhibitors (vildagliptin, linagliptin), immune checkpoint inhibitors (nivolumab, pembrolizumab), NSAIDs, antibiotics, ACE inhibitors, TNF inhibitors ^[4]

Pre-Immunosuppression Checklist — Critical in Hong Kong

Before starting any immunosuppressive therapy (steroids, azathioprine, rituximab, etc.), you MUST screen for:

HBsAg and anti-HBc ^[4] — HBV prevalence ~7–8% in HK; immunosuppression causes HBV reactivation → fulminant hepatitis → death. If positive, start entecavir/tenofovir prophylaxis
Fasting glucose / HbA1c — steroids worsen glycaemic control in diabetic patients (common in elderly HK population)
G6PD — if dapsone is planned (dapsone causes oxidative haemolysis; G6PD deficiency prevalence ~4.5% in HK males)
TPMT activity — if azathioprine is planned (TPMT deficiency → severe myelosuppression)
Baseline CBC, LRFT — for monitoring drug toxicity

Step 2: Disease-Severity-Stratified Treatment

Localised BP = blisters confined to a limited area (< 3 sites or small body surface area, up to 30% of BP cases).

Treatment	Regimen	Mechanism	Notes
Superpotent topical corticosteroids ^[1]^[7]	Clobetasol propionate 0.05% cream/ointment applied to affected areas BD	Potent local anti-inflammatory → suppresses complement-mediated inflammation and eosinophil recruitment at the BMZ; reduces protease release → ↓blister formation	First-line for localised disease; minimal systemic absorption when applied to limited areas
Oral doxycycline + nicotinamide ^[7]	Doxycycline 200 mg/day + nicotinamide (niacinamide) 500 mg TDS	Doxycycline: anti-inflammatory (inhibits matrix metalloproteinases, reduces eosinophil chemotaxis — independent of its antibiotic action). Nicotinamide: anti-inflammatory (inhibits mast cell degranulation, reduces neutrophil chemotaxis)	First-line agents per HKUMed dermatology teaching ^[9]; well-tolerated in elderly; avoids steroid side effects

Treatment	Regimen	Mechanism	Notes
Doxycycline ^[9]	200 mg/day (100 mg BD)	As above — anti-inflammatory, MMP inhibition	First-line are the tetracyclines ^[9]. BLISTER trial (2017) showed doxycycline was non-inferior to prednisolone at 6 weeks and had significantly fewer serious adverse events at 52 weeks
Topical potent corticosteroid ^[1]	Clobetasol propionate 0.05% to lesional areas	Local immunosuppression at lesion sites	Can be combined with doxycycline
Systemic corticosteroid ^[1]	Prednisolone 0.5 mg/kg/day ^[1]	Systemic suppression of autoimmune response — reduces autoantibody production, complement activation, inflammatory cell recruitment	Mainstay of initial treatment for moderate-severe disease ^[1]; dose is lower than for pemphigus (0.5 mg/kg/d vs 1–1.5 mg/kg/d) because BP is generally less aggressive

Mild-moderate: doxycycline, systemic corticosteroid (usually start with 0.5 mg/kg/d) — mainstay of initial treatment ^[1]

Treatment	Regimen	Mechanism	Notes
Systemic corticosteroid	Prednisolone 0.5 mg/kg/day ^[1]	As above	Begin tapering ≥ 1 week after the last formation of new blisters
OR superpotent topical CS	Clobetasol propionate 40 g/day to entire body ^[4]	Whole-body topical application provides systemic-level steroid effect via transcutaneous absorption, but with fewer systemic side effects than oral prednisolone	Superior to oral prednisone 1 mg/kg/d in the landmark NEJM study (76% vs 58% one-year survival) ^[3]^[4]; however, impractical in many settings — requires nursing staff to apply 3 tubes/day; > 1000 tubes/year ^[3]
Steroid-sparing immunosuppressive agent ^[1]	Azathioprine (preferred) or mycophenolate mofetil (MMF) ^[1]	Azathioprine: purine analogue → inhibits DNA synthesis in proliferating lymphocytes → ↓autoantibody production. MMF: inhibits inosine monophosphate dehydrogenase → selectively inhibits lymphocyte proliferation	Started upfront with steroids in some centres; in others, added at flares during steroid tapering or when refractory to steroids ^[8]. Allows steroid dose reduction → ↓steroid side effects

Steroid Tapering Protocol:

Begin tapering ≥ 1 week after the last formation of new lesions ^[8]
Typical taper: reduce by 5–10 mg every 1–2 weeks (slower taper = fewer relapses)
Steroid-sparing agent tapering: start tapering 8 weeks after completely off steroids ^[8]
Monitor: clinical response (new blister count), anti-BP180 titre (if available), eosinophil count

For patients who fail first- and second-line therapy:

Treatment	Mechanism	Evidence / Notes
Intravenous immunoglobulin (IVIg) ^[1]^[8]	Multiple mechanisms: Fc receptor blockade → ↓phagocytosis; anti-idiotypic antibodies neutralise pathogenic autoantibodies; modulation of complement activation	Consider IVIg for severe/refractory type ^[1]. Typically given as 2 g/kg over 2–5 days, repeated monthly. Expensive but well-tolerated
Rituximab ^[8]^[9]	Anti-CD20 monoclonal antibody → depletes B cells → ↓autoantibody production	Less evidence to support use in BP compared to pemphigus ^[9]; however, case reports/series show efficacy. Recently treated a patient with BP with rituximab, now in remission ^[9]. Gaining acceptance for refractory cases. Requires HBV screening
Cyclophosphamide ^[8]	Alkylating agent → potent immunosuppression; depletes both B and T lymphocytes	Reserved for refractory cases only due to significant toxicity (haemorrhagic cystitis, bone marrow suppression, malignancy risk)
Plasmapheresis / Immunoadsorption ^[8]	Physically removes circulating pathogenic IgG autoantibodies from plasma	Rapid but temporary effect; typically used as a bridge while awaiting slower-acting immunosuppressants to take effect
Dapsone ^[7]	Inhibits neutrophil chemotaxis and eosinophil function; anti-inflammatory	Useful steroid-sparing agent; contraindicated in G6PD deficiency (causes oxidative haemolysis). Must check G6PD before use — high prevalence of G6PD deficiency in HK
Methotrexate ^[7]	Anti-metabolite → inhibits dihydrofolate reductase → ↓lymphocyte proliferation	Steroid-sparing; useful in elderly who cannot tolerate azathioprine. Monitor LFT, CBC, renal function
Omalizumab (emerging)	Anti-IgE monoclonal antibody	Emerging evidence for BP with prominent eosinophilic/IgE-mediated component; not yet standard
Dupilumab (emerging)	Anti-IL-4Rα monoclonal antibody → blocks IL-4 and IL-13 (Th2 cytokines)	Targets the Th2-driven eosinophilic inflammation in BP; promising case reports; not yet in guidelines

Rituximab in BP vs Pemphigus

Rituximab has strong evidence and is increasingly used as upfront therapy in pemphigus vulgaris (where it has transformed outcomes). In bullous pemphigoid, the evidence is less robust ^[9], but clinical experience supports its use in refractory cases. The key teaching point: first-line for BP are the tetracyclines ^[9], not rituximab.

Drug	Class	Dose	Mechanism	Indications	Key Contraindications / Cautions	Monitoring
Clobetasol propionate	Superpotent topical CS (Group I)	0.05% cream/oint, BD to lesions; 40 g/day for extensive ^[4]	Binds glucocorticoid receptors → suppresses NF-κB → ↓cytokine/chemokine production → ↓inflammation and immune cell recruitment locally	First-line localised BP; alternative to oral steroids in extensive BP	Skin atrophy with prolonged use; avoid on face/flexures long-term; impractical for extensive disease (volume required)	Clinical response; skin atrophy
Prednisolone	Systemic CS	0.5 mg/kg/day ^[1]	Systemic anti-inflammatory and immunosuppressive; suppresses autoantibody production, complement, inflammatory cell function	Mainstay for moderate-severe/extensive BP ^[1]	DM (worsens glycaemia), osteoporosis, GI ulceration, infection risk, adrenal suppression, cataracts, psychosis	Blood glucose, BP, bone density, weight, infection surveillance
Doxycycline	Tetracycline antibiotic (used here for anti-inflammatory properties)	200 mg/day (100 mg BD)	Inhibits MMPs (matrix metalloproteinases — the proteases that destroy the BMZ); anti-inflammatory independent of antibiotic action; reduces eosinophil/neutrophil chemotaxis	First-line for mild-moderate BP ^[9]; BLISTER trial alternative to prednisolone	Oesophageal ulceration (take upright with water); photosensitivity; avoid in pregnancy; avoid in children < 12y (teeth staining)	Clinical response; GI tolerance
Nicotinamide	Vitamin B3 derivative	500 mg TDS	Inhibits mast cell degranulation; anti-inflammatory; reduces neutrophil chemotaxis; often synergistic with doxycycline	Adjunct to doxycycline for localised/mild BP	Generally well-tolerated; high-dose may cause hepatotoxicity, flushing	LFT if high doses
Azathioprine	Purine analogue (immunosuppressant)	1–3 mg/kg/day	Converted to 6-mercaptopurine → inhibits purine synthesis → ↓lymphocyte proliferation → ↓autoantibody production	Preferred steroid-sparing agent ^[8]	TPMT deficiency (check before starting — absent TPMT → severe myelosuppression); hepatotoxicity; pancreatitis; drug interaction with allopurinol (blocks xanthine oxidase → 6-MP accumulation → toxicity)	CBC weekly × 8 weeks then monthly; LFT; TPMT genotype/phenotype pre-treatment
Mycophenolate mofetil (MMF)	Inosine monophosphate dehydrogenase inhibitor	1–1.5 g BD	Selectively inhibits de novo purine synthesis in lymphocytes (lymphocytes lack the salvage pathway, so they are uniquely dependent on de novo synthesis) → ↓B and T cell proliferation	Alternative steroid-sparing agent ^[1]	GI side effects (diarrhoea, nausea); teratogenic (contraindicated in pregnancy); bone marrow suppression	CBC, LFT; pregnancy test before starting
Dapsone	Sulfone	50–150 mg/day	Inhibits neutrophil and eosinophil function; anti-inflammatory	Steroid-sparing agent; especially useful if prominent neutrophilic infiltrate	G6PD deficiency (absolute contraindication — causes severe haemolytic anaemia); methaemoglobinaemia; agranulocytosis	G6PD before starting; CBC, reticulocyte count, metHb levels
Methotrexate	Anti-metabolite (DHFR inhibitor)	7.5–15 mg/week	Inhibits dihydrofolate reductase → ↓DNA synthesis in rapidly dividing cells (lymphocytes); also ↑adenosine → anti-inflammatory	Steroid-sparing alternative	Hepatotoxicity; bone marrow suppression; pulmonary toxicity; renal impairment (reduced clearance); teratogenic. Give folic acid 5 mg/week to reduce side effects	CBC, LFT, RFT, CXR baseline
IVIg	Pooled human immunoglobulin	2 g/kg over 2–5 days	Multiple: Fc receptor blockade, anti-idiotypic Ab, complement modulation, cytokine modulation	Severe/refractory BP ^[1]	Renal impairment (osmotic nephropathy with sucrose-containing preparations); IgA deficiency (risk of anaphylaxis to IgA in IVIg); thrombotic risk	Renal function; IgA level pre-treatment; vital signs during infusion
Rituximab	Anti-CD20 monoclonal Ab	375 mg/m² × 4 weekly or 1000 mg × 2 (2 weeks apart)	Depletes CD20+ B cells → ↓autoantibody-producing B cell clones	Refractory BP ^[8]^[9]	HBV reactivation (screen HBsAg/anti-HBc); progressive multifocal leukoencephalopathy (rare); infusion reactions; hypogammaglobulinaemia	HBV screen; immunoglobulin levels; CBC; infection surveillance
Cyclophosphamide	Alkylating agent	1–2 mg/kg/day PO or IV pulse	Cross-links DNA → kills proliferating lymphocytes	Refractory only ^[8]	Haemorrhagic cystitis (give MESNA); bone marrow suppression; infertility; long-term malignancy risk (bladder cancer, lymphoma)	CBC, urinalysis, RFT

Parameter	Target	Rationale
Blister count	Presence of 5–10 blisters once every 1–2 weeks ^[7]	This is the treatment aim for BP — complete blister-free remission is ideal but not always achievable; accepting a low blister burden avoids overtreatment and steroid toxicity
New blister formation	No new blisters for ≥ 1 week before tapering	Indicates disease control sufficient to begin steroid reduction
Anti-BP180 titre	Falling titre	May correlate with disease activity ^[3]; rising titre on taper suggests impending relapse
Eosinophil count	Normalising	Reflects reduction in eosinophilic inflammation
Steroid side effects	Active surveillance	Blood glucose (esp. in DM), BP, bone density, cataracts, weight, mood, infection

6. Special Situations

Drug-induced bullous pemphigoid — implicated drugs: diuretics, dipeptidyl peptidase-4 inhibitors (vildagliptin, linagliptin), immune checkpoint inhibitors (nivolumab, pembrolizumab), NSAIDs, antibiotics, ACE inhibitors, TNF inhibitors ^[4]

First step: Identify and withdraw the implicated drug
Drug-induced BP may take weeks to months to resolve after drug withdrawal
If disease does not improve after drug withdrawal → treat as idiopathic BP
DPP-4 inhibitor-associated BP: switch to another class of diabetic agent (e.g. SGLT2 inhibitor, insulin)
PD-1 inhibitor-associated BP: decision to stop immunotherapy requires multidisciplinary discussion with oncology — stopping checkpoint inhibitors may compromise cancer treatment

Present in ~17% of BP patients ^[3]
Oral hygiene, soft diet, avoid irritating/acidic food
Topical oral corticosteroid (e.g. triamcinolone in Orabase)
Difflam (benzydamine) mouthwash for pain relief
May indicate need for systemic treatment escalation

Prefer doxycycline + topical CS over systemic steroids
Monitor closely for steroid side effects if systemic CS used
Lower threshold for switching to steroid-sparing agents
HBV screening mandatory before immunosuppression in HK

Step	Severity	Treatment
1	Localised	Superpotent topical CS (clobetasol) ± doxycycline + nicotinamide
2	Mild-moderate generalised	Doxycycline 200 mg/d ± topical CS ± prednisolone 0.5 mg/kg/d
3	Extensive / severe	Prednisolone 0.5 mg/kg/d (or topical clobetasol 40 g/d if feasible) + azathioprine or MMF
4	Refractory	IVIg, rituximab, cyclophosphamide, plasmapheresis
All	Supportive	Sterile aspiration (do NOT de-roof), antiseptic wound care, infection surveillance, drug review, oral care

High Yield Summary — Management of Bullous Pemphigoid

Immediate: prick but do NOT de-roof blisters; apply non-adhesive dressings; antiseptic wound cleansing ^[1]^[7]
Withdraw implicated drugs — especially gliptins, PD-1 inhibitors, diuretics, NSAIDs, ACE inhibitors, antibiotics, TNF inhibitors ^[4]
Pre-immunosuppression: HBsAg, anti-HBc, glucose, G6PD (if dapsone), TPMT (if azathioprine)
First-line: tetracyclines (doxycycline) — anti-inflammatory, not antibiotic effect ^[9]
Localised BP: superpotent topical CS (clobetasol) ± doxycycline + nicotinamide ^[7]
Moderate-severe: prednisolone 0.5 mg/kg/day — mainstay of initial treatment ^[1]
Topical clobetasol 40 g/day is superior to oral prednisone 1 mg/kg/day (NEJM: 76% vs 58% one-year survival) — but impractical (> 1000 tubes/year) ^[3]^[4]
Steroid-sparing agents: azathioprine (preferred) or MMF ^[1]^[8]
Refractory: IVIg, rituximab (less evidence than in pemphigus), cyclophosphamide ^[1]^[8]^[9]
Treatment aim: 5–10 blisters once every 1–2 weeks ^[7]
Taper steroids ≥ 1 week after no new blisters; taper steroid-sparing agent 8 weeks after off steroids ^[8]

Active Recall - Management of Bullous Pemphigoid

References

^[1] Lecture slides: CFB (MED09) Dermatology (II).pdf, p11 ^[3] Senior notes: Block A - Dermatology PBL 2.pdf, p3–4 ^[4] Lecture slides: Derm General Clerkship 2026 Part2.pdf, p25 ^[7] Senior notes: Maksim Medicine Notes.pdf, p71 ^[8] Senior notes: Ryan Ho Rheumatology.pdf, p153 ^[9] Senior notes: Block A - Treatments for skin diseases (eczema, psoriasis and urticaria).pdf, p6

Complications of Bullous Pemphigoid

Understanding complications in BP requires appreciating that this is a disease of the elderly and frail. Complications arise from three distinct sources:

The disease itself — skin barrier disruption, fluid loss, malnutrition
Secondary infection — the most immediately dangerous complication
Treatment-related iatrogenic complications — which, paradoxically, are the leading cause of morbidity and mortality in BP patients

Potentially fatal: 1-year overall mortality 11–48% ^[8]. This high mortality is driven primarily by the baseline frailty and comorbidities of the elderly population affected, compounded by treatment-related immunosuppression.

This is the most important acute complication of BP and the one you must actively surveil for.

Complication	Mechanism	Clinical Features	Management
Secondary bacterial infection (especially MRSA) ^[3]	Ruptured blisters and erosions expose the denuded dermis → loss of skin barrier → portal of entry for bacteria. Elderly, institutionalised patients (old-age home residents) have high MRSA colonisation rates	Worsening erythema/warmth around erosions; purulent discharge; failure of erosions to heal; fever; rising WBC/CRP. Suspect when all other erosions are healed, apart from one patch ^[3]	Wound swab for culture ^[7]; targeted antibiotics based on sensitivity; empirical anti-staphylococcal cover (e.g. flucloxacillin; vancomycin if MRSA suspected). Antibiotics if there is secondary bacterial infection ^[1]
Superimposed HSV-1 infection (eczema herpeticum-like) ^[3]	HSV-1 reactivation (common in elderly) preferentially infects denuded, damaged skin. Immunosuppressive treatment further increases risk	Monomorphic "punched-out" erosions or vesicles on an erythematous base; erosions that fail to heal despite appropriate wound care and antibiotics; suspect when all other erosions are healed, apart from one patch ^[3]	HSV/VZV PCR ^[4]; start IV aciclovir empirically if clinical suspicion is high; do not wait for PCR result
Cellulitis / bacteraemia / sepsis	Extension of local skin infection into deeper tissues or bloodstream; high risk in frail, immunosuppressed patients	Spreading erythema, systemic toxicity (fever, tachycardia, hypotension), septic shock	Blood cultures; IV broad-spectrum antibiotics; ICU if sepsis

The Non-Healing Erosion

Superimposed HSV1 + MRSA → suspect when all other erosions are healed, apart from one patch ^[3]. This is a critical clinical pearl: if a single erosion stubbornly refuses to heal while others are improving, you must consider superinfection with either bacteria (MRSA) or virus (HSV). Take a wound swab for bacterial culture AND viral PCR. Do not attribute non-healing to "refractory disease" without excluding infection first.

Complication	Mechanism	Clinical Features
Hypoalbuminaemia / protein loss	Extensive blistering → oozing serous fluid from ruptured bullae → loss of plasma proteins (albumin, immunoglobulins) through the disrupted skin barrier. Analogous to burn injury	Peripheral oedema, poor wound healing, increased susceptibility to infection
Dehydration / electrolyte disturbance	Insensible fluid loss through denuded skin surfaces (particularly in extensive disease); elderly patients have reduced thirst drive and may be on diuretics	Hypernatraemia, pre-renal AKI, confusion (especially dangerous in patients with baseline dementia)
Hypothermia	Loss of skin barrier → impaired thermoregulation (the skin is the body's largest thermoregulatory organ; loss of the epidermal barrier allows heat loss)	Particularly in bed-bound elderly; low core temperature, confusion

Why does this matter? The elderly BP population already has reduced physiological reserve. Even modest fluid or protein losses can tip them into decompensation — AKI, delirium, falls, and hospital-acquired complications.

Complication	Mechanism	Consequence
Poor oral intake / malnutrition	Oral mucosal erosions (present in ~17% of BP patients ^[3]) cause pain on eating and swallowing; severe pruritus and generalised illness → anorexia; hospital admission → poor diet	Weight loss, sarcopenia, impaired wound healing, ↑infection risk, ↑mortality. Dietitian input essential

Complication	Mechanism	Features
Post-inflammatory hyperpigmentation	Melanocyte stimulation by dermal inflammation; melanin "drops" into the dermis after the inflammatory process resolves	Brownish discolouration at sites of healed blisters. More prominent in darker-skinned individuals (common in HK Chinese population). Cosmetically distressing but not medically dangerous; fades slowly over months
Milia formation	Blisters and erosions may heal with milia formation in bullous pemphigoid ^[4]	Small (1–2 mm) white or yellowish keratin-filled cysts at sites of healed blisters. Occur because the healing process traps small epithelial fragments within the dermis. More commonly associated with EBA but can occur in BP
Scarring	Generally minimal or absent in BP (unlike EBA where scarring is prominent) — because the subepidermal split in BP heals by re-epithelialisation from the preserved blister roof and adnexal structures	Significant scarring is unusual in BP; if prominent scarring or milia are present, reconsider the diagnosis (think EBA)

This is where the bulk of the mortality comes from. Treatment-related complications are the most important cause of death in BP, accounting for more deaths than the disease itself.

Systemic corticosteroids (prednisolone 0.5 mg/kg/day) are the mainstay of initial treatment ^[1] for moderate-severe disease, but carry enormous risk in the elderly.

Complication	Mechanism	Why It Is Especially Dangerous in BP Patients
Infection (most important)	Steroids suppress innate and adaptive immunity → ↓neutrophil function, ↓T-cell-mediated immunity, ↓cytokine production	Elderly BP patients are already immunocompromised by age and comorbidities; adding steroids dramatically increases risk of pneumonia, UTI, sepsis, opportunistic infections (PJP, TB reactivation, candidiasis). Immunosuppression risk ^[3] — pentamidine inhalation for patients who cannot tolerate septrin (co-trimoxazole) for PJP prophylaxis ^[3]
Hyperglycaemia / steroid-induced diabetes	Glucocorticoids → ↑hepatic gluconeogenesis, ↑insulin resistance, ↓peripheral glucose uptake	Many elderly BP patients already have diabetes or prediabetes; steroids worsen control → DKA/HHS risk. Monitor blood glucose frequently
Osteoporosis / fragility fractures	Steroids → ↓osteoblast function, ↑osteoclast activity, ↓calcium absorption, ↓sex hormones → ↓bone density	Elderly patients (especially post-menopausal women) already have osteoporosis → steroid use dramatically increases fracture risk (hip, vertebral). Start calcium + vitamin D ± bisphosphonate if prolonged steroid use anticipated
Adrenal suppression	Exogenous steroids suppress the HPA axis → adrenal atrophy → inability to mount cortisol stress response	Risk of adrenal crisis with abrupt steroid withdrawal or during intercurrent illness. Always taper gradually
GI complications	↓mucosal protection, ↑gastric acid → peptic ulceration; combined with NSAIDs = synergistic risk	Prescribe PPI prophylaxis if concurrent NSAID use or GI risk factors
Skin atrophy	Steroids → ↓collagen synthesis, ↓dermal thickness	Skin already compromised by blistering disease; further atrophy → ↑fragility → ↑blister risk (vicious cycle)
Cataracts / glaucoma	Posterior subcapsular cataracts with chronic steroid use; raised IOP	Ophthalmological review if prolonged steroid course
Psychiatric effects	Steroid psychosis, insomnia, agitation, depression	Particularly problematic in patients with baseline dementia (common in BP population)
Hypertension / fluid retention	Mineralocorticoid effect → Na+ retention, K+ loss	Monitor BP and electrolytes
Myopathy	Proximal muscle wasting (steroid myopathy)	Compound existing sarcopenia in the elderly → ↑falls risk → ↑fractures

This is precisely why topical clobetasol propionate was superior to oral prednisone in the NEJM trial — one-year survival 76% vs 58% ^[4] — the difference is driven by fewer systemic steroid side effects in the topical group.

PJP Prophylaxis

Immunosuppression risk is a major concern ^[3]. For patients on high-dose or prolonged systemic steroids (> 20 mg prednisolone for > 4 weeks) + another immunosuppressant: consider Pneumocystis jirovecii pneumonia (PJP) prophylaxis with co-trimoxazole (TMP-SMX). Pentamidine inhalation for patients who cannot tolerate septrin ^[3].

Complication	Mechanism	Notes
Cutaneous atrophy, striae, folliculitis ^[8]	Prolonged superpotent topical steroid application → ↓collagen synthesis → skin thinning, telangiectasia, striae	Particularly problematic in flexural areas; less of a concern with short courses
Adrenal suppression (if extensive application) ^[8]	Whole-body application of 40 g/day clobetasol → significant transcutaneous absorption → systemic steroid levels	This is why the NEJM regimen, while effective, causes some systemic effects despite being "topical"
Impracticality	Not a medical complication per se, but a practical one	Not feasible — 3 tubes a day, more than 1000 tubes per year ^[3]. Requires dedicated nursing time; patients cannot self-apply to back/extensive areas

Drug	Key Complications	Monitoring
Azathioprine	Bone marrow suppression (especially if TPMT deficiency → severe myelosuppression); hepatotoxicity; pancreatitis; increased infection risk; drug interaction with allopurinol (blocks xanthine oxidase → 6-MP accumulation → life-threatening pancytopenia)	TPMT genotype before starting; CBC weekly × 8 weeks then monthly; LFT
Mycophenolate mofetil	GI side effects (diarrhoea, nausea — most common); bone marrow suppression; teratogenic (pregnancy contraindicated)	CBC, LFT; pregnancy test
Dapsone	Haemolytic anaemia (especially in G6PD deficiency — absolute contraindication); methaemoglobinaemia; agranulocytosis; peripheral neuropathy	G6PD before starting; CBC, reticulocytes, methaemoglobin levels
Methotrexate	Hepatotoxicity; bone marrow suppression; pulmonary fibrosis; mucositis; teratogenic; accumulates in renal impairment (common in elderly)	CBC, LFT, RFT; give folic acid 5 mg weekly
Cyclophosphamide	Haemorrhagic cystitis (give MESNA); bone marrow suppression; infertility; ↑long-term malignancy risk (bladder cancer, lymphoma)	CBC, urinalysis; hydration

Complication	Mechanism
HBV reactivation	B-cell depletion removes immune surveillance of latent HBV → viral replication → fulminant hepatitis. Mandatory HBV screening before use
Progressive multifocal leukoencephalopathy (PML)	JC virus reactivation due to profound immunosuppression; rare but devastating
Hypogammaglobulinaemia	Sustained B-cell depletion → ↓immunoglobulin production → ↑infection risk
Infusion reactions	Cytokine release during infusion; premedicate with paracetamol + antihistamine + methylprednisolone

Rituximab: less evidence to support its use and greater risk due to the age of the population ^[10]

Because BP preferentially affects elderly patients with neurological disease, many complications reflect the interaction between BP and baseline comorbidities:

Complication	Mechanism
Falls and immobility	Pruritus → sleep deprivation → confusion; steroid myopathy → weakness; pain from blisters → reduced mobility; all compound baseline frailty and neurological disease (dementia, Parkinson's, stroke) → ↑falls → fractures
Delirium	Infection, dehydration, electrolyte disturbance, steroid psychosis, hospitalisation in a patient with baseline dementia → precipitant upon precipitant for delirium
Venous thromboembolism	Immobility + inflammation + hospitalisation → ↑VTE risk. Consider DVT prophylaxis
Pressure injuries	Bed-bound patients with extensive blistering have compromised skin integrity → pressure ulcers develop rapidly
Hospital-acquired infections	Prolonged hospital stays in immunosuppressed elderly patients → MRSA, C. difficile, hospital-acquired pneumonia

Factor	Detail
1-year overall mortality	11–48% ^[8] — highly variable depending on patient population, comorbidities, and treatment
Cause of death	Predominantly from treatment-related complications (infection from immunosuppression, steroid side effects) and baseline comorbidities — NOT the blistering disease per se
Clinical course	Variable; usually follows a chronic, relapsing course with long-term remission months to years after initial onset ^[8]
Self-remission	Some patients achieve spontaneous remission, but timing is unpredictable (months to years)
Predictors of poor prognosis	Advanced age, extensive disease, high anti-BP180 titre, comorbid neurological disease, need for systemic steroids, nosocomial infections

Mnemonic: Complications of BP — 'BLISTERS'

B — Bacterial superinfection (MRSA) and viral (HSV)
L — Loss of fluid and protein (hypoalbuminaemia, dehydration)
I — Iatrogenic (steroid side effects — THE major killer)
S — Sepsis (from skin barrier breach + immunosuppression)
T — Thromboembolism (immobility + inflammation)
E — Eating difficulty (oral erosions → malnutrition)
R — Reactivation of HBV (from immunosuppressive treatment)
S — Skin changes (post-inflammatory hyperpigmentation, milia, atrophy from steroids)

High Yield Summary — Complications of Bullous Pemphigoid

Secondary infection is the most important acute complication: MRSA and HSV-1 superinfection ^[3]. Suspect when one erosion refuses to heal while others improve.
Treatment-related complications (especially systemic steroids) are the leading cause of death: infection, hyperglycaemia, osteoporosis, adrenal suppression, GI ulceration.
1-year mortality is 11–48% ^[8] — driven by treatment complications and baseline frailty, not the blisters themselves.
Topical steroids are superior to oral steroids (76% vs 58% one-year survival) ^[4] — because they avoid systemic steroid toxicity.
PJP prophylaxis with co-trimoxazole (or pentamidine inhalation if intolerant ^[3]) should be considered for patients on prolonged systemic immunosuppression.
Milia formation can occur at sites of healed blisters ^[4]; prominent scarring should prompt reconsideration of the diagnosis (think EBA).
Screen for HBV before immunosuppression; check G6PD before dapsone; check TPMT before azathioprine.
Fluid/protein loss, malnutrition, delirium, falls, VTE, and pressure injuries are important comorbidity-related complications in this elderly, frail population.

Active Recall - Complications of Bullous Pemphigoid

References

^[1] Lecture slides: CFB (MED09) Dermatology (II).pdf, p11 ^[3] Senior notes: Block A - Dermatology PBL 2.pdf, p3–4 ^[4] Lecture slides: Derm General Clerkship 2026 Part2.pdf, p21, p25 ^[7] Senior notes: Maksim Medicine Notes.pdf, p71 ^[8] Senior notes: Ryan Ho Rheumatology.pdf, p154 ^[10] Lecture slides: GC 090. Treatments for skin diseases.pdf, p16

High Yield Summary

Bullous Pemphigoid — Key Points for Exams:

Most common autoimmune blistering disease; predominantly affects elderly (> 60y, median ~80y)
Autoantibodies against BP180 (NC16A domain) and BP230 at hemidesmosomes → subepidermal split → tense bullae
Tense blisters on an erythematous, urticarial base (cf. pemphigus = flaccid blisters)
Nikolsky sign NEGATIVE (epidermis intact; split is at DEJ)
Pre-bullous phase mimics eczema or urticaria — suspect BP if urticaria > 24 hours
Associated with neurological disease (stroke, dementia, Parkinson's) — BP180/230 expressed in CNS
Drug triggers: DPP-4 inhibitors (gliptins) and PD-1 inhibitors (pembrolizumab)
Mucosal involvement in ~10–30% (usually oral; less prominent than pemphigus)
Eosinophilia may be present; eosinophilic infiltrate is characteristic histologically
Diagnosis: perilesional biopsy → H&E (subepidermal split) + Direct IF (linear IgG and C3 at DEJ) + Serology (anti-BP180/BP230 ELISA)
Blister roof should NOT be de-roofed — puncture only to relieve tension
Erythematous base distinguishes BP from oedema blisters (CHF, cirrhosis)
First-line treatment: tetracyclines (for mild-moderate) or topical/systemic corticosteroids; topical steroids may be better than oral steroids (NEJM evidence)

High Yield Summary — Differential Diagnosis of Bullous Pemphigoid

Pre-bullous phase DDx: urticaria (resolves < 24h), urticarial vasculitis (painful, purpura, persists > 24h), eczema, drug eruption, viral exanthem, bites/papular urticaria, scabies
Bullous phase DDx (tense blisters): BP, contact dermatitis, insect bite reactions, epidermolysis bullosa acquisita ^[4]
Bullous phase DDx (flaccid blisters/erosions): pemphigus vulgaris, SJS/TEN, paraneoplastic pemphigus ^[4]
Key distinguishing features of BP: tense blisters, Nikolsky −ve, erythematous base, heals without scarring, linear IgG/C3 at DEJ on DIF, anti-BP180/230
Oedema blisters (CHF/cirrhosis) mimic BP — differentiate by absence of surrounding erythema ^[3]
EBA mimics BP on standard DIF — differentiate by salt-split skin (EBA = dermal floor; BP = epidermal roof) and clinical features (EBA scars with milia, acral)
Always rule out drug-induced BP — especially DPP-4 inhibitors and PD-1 inhibitors ^[1]

High Yield Summary — Investigations for Bullous Pemphigoid

Diagnosis is clinical, confirmed with skin biopsy and serology ^[1]
Two biopsies needed: lesional skin → H&E (subepidermal split + eosinophils); perilesional skin → DIF (linear IgG/C3 along BMZ — gold standard) ^[1]^[4]
Blood workup (GC 2026): CBC, LRFT, fasting glucose, HbA1c, HBsAg, anti-HBc, anti-skin antibody, anti-BP180, anti-BP230 ELISA ^[4]
DIF is the gold standard: linear C3 (~100%) and IgG (> 90%) along DEJ ^[4]
Salt-split skin: distinguishes BP (epidermal/roof side) from EBA (dermal/floor side)
Anti-BP180 ELISA: most sensitive and specific serological test; may correlate with disease activity ^[3]
Always rule out drug-induced BP and screen for HBV before immunosuppression ^[1]^[4]
Anti-BP180/BP230 ELISA not available at QMH ^[4] — rely on anti-skin antibody + DIF at QMH

High Yield Summary — Management of Bullous Pemphigoid

Immediate: prick but do NOT de-roof blisters; apply non-adhesive dressings; antiseptic wound cleansing ^[1]^[7]
Withdraw implicated drugs — especially gliptins, PD-1 inhibitors, diuretics, NSAIDs, ACE inhibitors, antibiotics, TNF inhibitors ^[4]
Pre-immunosuppression: HBsAg, anti-HBc, glucose, G6PD (if dapsone), TPMT (if azathioprine)
First-line: tetracyclines (doxycycline) — anti-inflammatory, not antibiotic effect ^[9]
Localised BP: superpotent topical CS (clobetasol) ± doxycycline + nicotinamide ^[7]
Moderate-severe: prednisolone 0.5 mg/kg/day — mainstay of initial treatment ^[1]
Topical clobetasol 40 g/day is superior to oral prednisone 1 mg/kg/day (NEJM: 76% vs 58% one-year survival) — but impractical (> 1000 tubes/year) ^[3]^[4]
Steroid-sparing agents: azathioprine (preferred) or MMF ^[1]^[8]
Refractory: IVIg, rituximab (less evidence than in pemphigus), cyclophosphamide ^[1]^[8]^[9]
Treatment aim: 5–10 blisters once every 1–2 weeks ^[7]
Taper steroids ≥ 1 week after no new blisters; taper steroid-sparing agent 8 weeks after off steroids ^[8]

High Yield Summary — Complications of Bullous Pemphigoid

Secondary infection is the most important acute complication: MRSA and HSV-1 superinfection ^[3]. Suspect when one erosion refuses to heal while others improve.
Treatment-related complications (especially systemic steroids) are the leading cause of death: infection, hyperglycaemia, osteoporosis, adrenal suppression, GI ulceration.
1-year mortality is 11–48% ^[8] — driven by treatment complications and baseline frailty, not the blisters themselves.
Topical steroids are superior to oral steroids (76% vs 58% one-year survival) ^[4] — because they avoid systemic steroid toxicity.
PJP prophylaxis with co-trimoxazole (or pentamidine inhalation if intolerant ^[3]) should be considered for patients on prolonged systemic immunosuppression.
Milia formation can occur at sites of healed blisters ^[4]; prominent scarring should prompt reconsideration of the diagnosis (think EBA).
Screen for HBV before immunosuppression; check G6PD before dapsone; check TPMT before azathioprine.
Fluid/protein loss, malnutrition, delirium, falls, VTE, and pressure injuries are important comorbidity-related complications in this elderly, frail population.

Bullous Pemphigoid

1. Definition

2. Epidemiology

3. Anatomy and Function of the Dermal–Epidermal Junction

3.1 Structure of the Basement Membrane Zone (BMZ)

3.2 Hemidesmosomes — The Target in BP

3.3 Function

4. Aetiology and Risk Factors

4.1 Primary Aetiology: Autoimmune

4.2 Risk Factors and Triggers

4.3 Hong Kong Context

5. Pathophysiology

Step 1: Loss of Tolerance and Autoantibody Production

Step 2: Autoantibody Binding at the DEJ

Step 3: Complement Activation

Step 4: Inflammatory Cell Infiltration and Protease Release

Step 5: Subepidermal Blistering

6. Classification

6.1 Clinical Phases

6.2 Clinical Subtypes / Variants

6.3 Comparison with Other Autoimmune Blistering Diseases

7. Clinical Features

7.1 Symptoms

7.2 Signs

A. Pre-Bullous Phase Signs

B. Bullous Phase Signs

C. Distribution

D. Special Signs and Clinical Pearls

7.3 Clinical Course

8. Associated Conditions

Active Recall - Bullous Pemphigoid (Definition, Epidemiology, Pathophysiology, Clinical Features)

References

1. Clinical Reasoning Framework

2. Differential Diagnosis by Phase

2.A Pre-Bullous Phase Differentials (No Blisters Yet)

2.B Bullous Phase Differentials (Blisters Present)

3. Approach to Narrowing the Differential

4. Key Differentiating Investigations (Preview)

5. Summary Comparison Table — The "Big Five" Blistering Differentials

6. Differential by Distribution (from Ryan Ho) [2]

Active Recall - Differential Diagnosis of Bullous Pemphigoid

1. Diagnostic Criteria

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 Bedside Assessment

3.2 Blood Investigations

Additional Bloods for Specific Scenarios (from GC 2026 slides) [4]

3.3 Skin Biopsy — The Diagnostic Cornerstone

Biopsy 1: Lesional Skin → H&E Histopathology

Biopsy 2: Perilesional Skin → Direct Immunofluorescence (DIF)

Salt-Split Skin Technique

3.4 Serology — Indirect Immunofluorescence and ELISA

3.5 Additional Investigations

4. Interpreting Results — Putting It All Together

5. Monitoring Disease Activity

Active Recall - Diagnosis and Investigations for Bullous Pemphigoid

1. Principles of Management

2. Management Algorithm

3. Step-by-Step Management

Step 1: Immediate / Supportive Measures (All Patients)

Step 2: Disease-Severity-Stratified Treatment

A. Localised Bullous Pemphigoid

B. Mild-Moderate Generalised Bullous Pemphigoid

C. Extensive / Severe Bullous Pemphigoid

D. Refractory Bullous Pemphigoid

4. Treatment Modalities — Detailed Pharmacology

5. Treatment Targets and Monitoring

6. Special Situations

Drug-Induced Bullous Pemphigoid

Mucosal Involvement

Elderly / Frail Patients

7. Summary of Treatment Ladder

Active Recall - Management of Bullous Pemphigoid

1. Disease-Related Complications

1.1 Secondary Infection

1.2 Fluid and Protein Loss

1.3 Nutritional Compromise

1.4 Post-Inflammatory Changes

2. Treatment-Related Complications

2.1 Systemic Corticosteroid Complications